Method and system for cell operations using the internet of things

ABSTRACT

A data collection hub and method wherein a controller is configured to receive data from a plurality of sensors sensing conditions related to the performance of operations on cells by at least one instrument. A database stores the data from the plurality of sensors and the controller is configured to compare data from the plurality of sensors for a past operation with the data for a more recent operation.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of non-provisional applicationSer. No. 16/671,308, filed Nov. 1, 2019, now issued as U.S. Pat. No.11,230,690, which in turn is a continuation-in-part of non-provisionalapplication Ser. No. 15/773,651 filed May 4, 2018, now issued as U.S.Pat. No. 11,118,154, and which claims priority to PCT/US16/60722 filedNov. 4, 201[0]6 and which in turn claims priority to provisionalapplication No. 62/250,986, filed on Nov. 4, 2015, and which is relatedto U.S. provisional applications No. 62/141,183, filed on Mar. 31, 2015;62/141,187, filed on Mar. 31, 2015; 62/141,191, filed on Mar. 31, 2015;and 62/141,196, filed on Mar. 31, 2015, the entire disclosure of each ofwhich is hereby incorporated by reference as if set forth in itsentirety herein.

FIELD

Embodiments described herein relate generally to methods and systems forperforming cell operations such as cell imagers and cell incubators, andin particular to cell culture incubators that can be configured tooperate, at least in part, utilizing parameter data received through anetwork interface that may be gathered by at least one other incubator.

BACKGROUND

Cell culture incubators are used to grow and maintain cells from cellculture, which is the process by which cells are grown under controlledconditions. Cell culture vessels containing cells are stored within theincubator, which maintains conditions such as temperature and gasmixture that are suitable for cell growth. Cell imagers take images ofindividual or groups of cells for cell analysis.

Long-term cell culture is a useful technique in both research andclinical contexts. However, maintenance of long-term cell cultures, forexample, long term cultures, tissue preparations, in vitro fertilizationpreparations, etc., in presently available cell incubators is alaborious process requiring highly trained personnel and stringentaseptic conditions. This high level of human involvement can introducecontaminants into the culture and cause shock from environmentalchanges, thereby lowering culture efficiency. Cell imagers are usefulfor research and for cell manufacturing.

Accordingly, new types of methods and systems for performing celloperations such as cell culture incubators that provide a culture systemwith reduced human involvement are needed.

SUMMARY

This summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription section. This summary is not intended to identify keyfeatures or essential features of the claimed subject matter, nor is itintended to be used as an aid in determining the scope of the claimedsubject matter.

Conventional cell culture incubators impose several barriers toproductive long-term cell culture, particularly for purposes ofmaintaining cells for clinical purposes or for research purposesinvolving sensitive assays, e.g., for evaluating drug function orinterrogating cellular function. For example, many presently availablecell incubators require extensive operator interaction to load andunload culture plates, to move cell culture vessels, to supplysterilization medium, etc. Unfortunately, human operators introduce thepossibility of human error, contamination, etc. Thus, the disclosure inpart relates to a cell culture incubator that reduces human error byreceiving parameter data controlling its operation derived fromparameter data successfully used by other incubators and using theinternet of things to further reduce the errors.

The internet of things by way of example for the present field, is thenetwork of devices such as sensors, actuators, software and circuitrywhich is internal and/or external to cell operations instruments whichall these things to connect, interact and exchange information. Theinternet of things is can be implemented with current Wi-Fi, Bluetoothand cellular protocols, but will be particularly improved by the use of5G cellular, Bluetooth low energy and the 60 GHz range of Wi-Fi alsocalled WiGig which is 802.11ad and 802.11ay. WiGig allows wireless highdata rate transfers for line of sight connections, which areparticularly useful in a laboratory where instruments and materials foruse with the instruments are stored.

One object of the invention is to maintain an archival history of theambient conditions of the laboratory, the storage and conditions of thematerials, the identification of operators and the use of theinstruments. The data from multiple sensors including proximity sensors,temperature sensors, RFID devices and bar codes can populate thatarchive. Thereafter, if one were to compare tests run on an instrumentto earlier tests run either on the same instrument or anotherinstrument, one can also compare the archived data to see anydifferences that would account for differences in results.

According to one aspect of the disclosure, embodiments of the presentinvention relate to a non-transitory computer-readable medium havinginstructions stored thereon for performing a method of facilitatingnetworked incubator operation. In some embodiments, the medium includesinstructions operable on one or more processors for receiving, from afirst networked incubator system, data that comprises incubatoroperating parameters for operating a networked incubator system; storingthe received parameter data in a database; receiving a query forincubator operating parameters from a second networked incubator system;and transmitting, from the database in response to the received queryfrom the second networked incubator system, parameter data thatcorresponds to the data received from the first networked incubatorsystem and is arranged to control operation of the second networkedincubator system.

In one embodiment, the received parameter data and the transmittedparameter data each comprise at least one of: an image, informationderived from an image, a step in a process for incubator operation,temperature data, cell type data, time data, cell growth data, andgrowth medium data.

In one embodiment, the medium further includes instructions storedthereon for approving the query from the second incubator system priorto the transmission of parameter data.

In one embodiment, the non-transitory computer-readable medium furtherhas instructions stored thereon for sending a query for parameter datato a server. In some embodiments, the non-transitory computer-readablemedium has instructions stored thereon for sending authenticationcredentials in connection with a query for parameter data to a server.

In one embodiment, the medium further includes for anonymizing thereceived parameter data so that the first networked incubator systemcannot be identified from the transmitted parameter data.

In one embodiment, the medium further includes instructions forcomputing values derived from the received parameter data. In oneembodiment, the derived values are selected from the group consisting ofcompilations, statistics, and values that correspond to a deep learningnetwork.

In one embodiment, the query received from the second networkedincubator system comprises at least one of: an image, informationderived from an image, a step in a process for incubator operation,temperature data, cell type data, time data, cell growth data, andgrowth medium data.

In one embodiment, the first networked incubator system and the secondnetworked incubator system are the same networked incubator system.

According to another aspect, embodiments relate to a method offacilitating networked incubator operation. The method includesreceiving, from a first networked incubator system, data comprisingincubator operating parameters for operating a networked incubatorsystem; storing, in a non-transitory memory, the received parameter datain a database; receiving, from a second networked incubator system, aquery for incubator operating parameters; and transmitting parameterdata from the database in response to the received query, the parameterdata corresponding to the data received from the first networkedincubator system and arranged to control operation of the secondnetworked incubator system.

In one embodiment, the query received from the second networkedincubator system includes at least one of: an image, information derivedfrom an image, a step in a process for incubator operation, temperaturedata, cell type data, time data, cell growth data, and growth mediumdata.

In one embodiment, the received parameter data and the transmittedparameter data each comprise at least one of: an image, informationderived from an image, a step in a process for incubator operation,temperature data, cell type data, time data, cell growth data, andgrowth medium data.

In one embodiment, the method further includes approving the query fromthe second incubator system prior to the transmission of parameter data.

In one embodiment, the method further includes anonymizing the receivedparameter data so that the first networked incubator system cannot beidentified from the transmitted parameter data.

In one embodiment, the method further includes computing values derivedfrom the received parameter data. In one embodiment, the derived valuesare selected from the group consisting of compilations, statistics,values that correspond to a deep learning network, etc.

In one embodiment, the query received from the second networkedincubator system comprises at least one of: an image, informationderived from an image, a step in a process for incubator operation,temperature data, cell type data, time data, cell growth data, andgrowth medium data.

In one embodiment, the first networked incubator system and the secondnetworked incubator system are the same networked incubator system.

According to yet another aspect, embodiments of the present inventionrelate to a cell culture incubator system. The system includes adatabase; a first networked incubator in operable communication with thedatabase, wherein the first networked incubator is configuredcommunicate data regarding at least one operating parameter related tothe operation of the first networked incubator; and a second networkedincubator in operable communication with the database, wherein thesecond networked incubator is configured to receive data regarding theat least one operating parameter of the first networked incubator, andfurther configured to control operation of the second networkedincubator based on the data regarding the at least one operatingparameter.

In one embodiment, the data regarding the at least one operatingparameter comprises at least one of: an image, information derived froman image, a step in a process for incubator operation, temperature data,cell type data, time data, cell growth data, and growth medium data.

In one embodiment, the second networked incubator further hasinstructions stored thereon for sending a query for parameter data tothe database.

In one embodiment, the second networked incubator further hasinstructions stored thereon for sending authentication credentials inconnection with a query for parameter data to a server.

According to yet another aspect, embodiments of the present inventionrelate to a method of facilitating networked incubator operation. Insome embodiments, the method includes receiving, from a first networkedincubator system, data comprising incubator operating parameters foroperating a networked incubator system. In some embodiments, the methodincludes storing, in a non-transitory memory, the received parameterdata in a database. In some embodiments, the method includes receiving,from a second networked incubator system, a query for incubatoroperating parameters. In some embodiments, the method includestransmitting parameter data from the database in response to thereceived query, the parameter data corresponding to the data receivedfrom the first networked incubator system and arranged to controloperation of the second networked incubator system.

Other embodiments are a data collection method and a data collection hubcomprising a controller configured to receive data from a plurality ofsensors sensing conditions related to the performance of operations oncells by at least one instrument. Operations on cells includes for thepurposes of example: imaging, counting, moving, adding reagent,measuring, processing data from measuring or counting, processing datafrom imaging, and incubating. This assists with best practices, GoodManufacturing Practices, Good Laboratory Practices and equivalents. Itseems like we don't mention the need for recording all that happens in acell culture lab for documentation, regulatory, quality control, qualityassurance, identifying sources of variability and contamination. Thismethod and apparatus are suitable for long-term, short-term and mediumterm cultures.

Data relating to the performance of operations on cells includes assaydata, human interpretation, motion data (such as the movements ofoperators, data from incubators, microscopes and other lab equipment,data from other instruments that are collecting data in the cell culturelab or even outside of it, cell count, cell metabolism measurements, andsequence data performed in or outside the lab. Data can include videos,sound, status of the operators, history and data of experiments oncells, things that have been added to the cells beyond media,environmental data, including air purity or humidity, security data suchas perimeter alarms, motion detectors, water leaks, earthquakes, brokenwindows, noise from breaking and entering.

The hub receives data from the plurality of sensors, wherein thecontroller is configured to store the data in a database and in oneembodiment compare data from the plurality of sensors for a pastoperation with the data for a more recent operation to account for anydifferences in the results of the more recent operation.

In some embodiments the plurality of sensors includes at least oneproximity sensor for sensing when a closure for a container of amaterial used in a cell operation has been removed, at least oneproximity sensor for sensing when material used in a cell operation hasbeen removed from a liquid nitrogen tank, at least one proximity sensorfor sensing when a plate used in a cell operation has been removed froma refrigerator, and/or at least one temperature sensor for sensingambient temperature conditions. In some embodiments, proximity sensorssense when a cover has been removed from a plate, the location of abottle or a plate, the time when operations are performed, the locationof the instrument, sounds in the vicinity of the instrument and otherrelevant information.

In some embodiments the hub includes at least one infrared camera, videocamera or other camera for filming in the vicinity of at least one celloperations instrument, a bar code reader for reading bar codes onarticles used for cell operations, an RFID reader for reading RFID tagson at least one of people or materials in the vicinity of at least onecell operations instrument, a Bluetooth transceiver, a Wi-Fi transceiverand/or a network interface for receiving data from at least oneinstrument for performing cell operations.

In some embodiments, a hub can be associated with a single instrument ora plurality of instruments. Alternatively, hubs can be situatedthroughout a laboratory and the hubs can be networked to each other. Thedata from the networked hubs can be stored in a database and at leastone server can be provided to analyze the data and/or provide regulatoryand tracking information.

In one embodiment a data collection hub comprises a controllerconfigured to receive data from a plurality of sensors sensingconditions related to the performance of operations on cells by at leastone instrument including at least one sensor on the instrument and atleast one sensor on supplies used in conjunction with the instrument, adatabase for storing the data from the plurality of sensors and whereinthe controller is configured to store data from the plurality of sensorsin the database.

In another embodiment, a data collection method comprises the steps ofconfiguring a controller to receive data from a plurality of sensorssensing conditions related to the performance of operations on cells byat least one instrument including at least one sensor on the instrumentand at least one sensor on supplies used in conjunction with theinstrument and storing the data from the plurality of sensors in adatabase.

In some embodiments of the method and hub, the conditions related to theperformance of operations on cells includes measurements of status ofcells and cell environment. In addition, the conditions related to theperformance of operations on cells can include alerts and the lerts canbe to people and/or other computers.

In some embodiments of the method and hub, the controller is configuredto capture multiple streams of data. In addition, the controller isconfigured to capture multiple streams of data, analyze the data andtransmit the analysis. In some embodiments of the method and hub, thecontroller is configured compare data from the plurality of sensors fora past operation with the data for a more recent operation to accountfor any differences in the results of the more recent operation.

In some embodiments of the method and hub, the plurality of sensorsincludes at least one proximity sensor for sensing when a closure for acontainer of a material used in a cell operation has been removed. Insome embodiments of the method and hub, the plurality of sensorsincludes at least one proximity sensor for sensing when material used ina cell operation has been removed from a liquid nitrogen tank. In someembodiments of the method and hub, the plurality of sensors includes atleast one proximity sensor for sensing when a plate used in a celloperation has been removed from a refrigerator. In some embodiments ofthe method and hub, the plurality of sensors includes at least oneproximity sensor for sensing when a cover has been removed from a plate.In some embodiments of the method and hub, the plurality of sensorsincludes at least one sensor on a base and one on a cover to indicatewhen the cover has been removed.

In some embodiments of the method and hub, a sensor on each of aplurality of bottles provides location information for each of theplurality of bottles. In some embodiments of the method and hub, theplurality of sensors includes at least one temperature sensor forsensing ambient temperature conditions. In some embodiments of themethod and hub, they further comprise at least one video camera forfilming in the vicinity of at least one cell operations instrument, atleast one microphone for recording sound, a global positioning systemreceiver for providing location information, a clock for providing timeinformation, a code reader for reading codes on articles used for celloperations and/or an RFID reader for reading RFID tags on at least oneof people or materials in the vicinity of at least one cell operationsinstrument.

In some embodiments of the method and hub, they further comprise aBluetooth transceiver, a Wi-Fi transceiver, a network interface forreceiving data from at least one instrument for performing celloperations, and/or a network interface for receiving data from at leastone other data collection hub.

Sensors for collecting data relating to the performance of operations oncells includes sensors for assay data, human interpretation, motion data(such as the movements of operators, data from incubators, microscopesand other lab equipment, data from other instruments that are collectingdata in the cell culture lab or even outside of it, cell count, cellmetabolism measurements, and sequence data performed in or outside thelab. Data can include videos, sound, status of the operators, historyand data of experiments on cells, things that have been added to thecells beyond media, environmental data, including air purity orhumidity, security data such as perimeter alarms, motion detectors,water leaks, earthquakes, broken windows, noise from breaking andentering.

These and other features and advantages, which characterize the presentnon-limiting embodiments, will be apparent from a reading of thefollowing detailed description and a review of the associated drawings.It is to be understood that both the foregoing general description andthe following detailed description are explanatory only and are notrestrictive of the non-limiting embodiments as claimed.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings are not intended to be drawn to scale. In thedrawings, each identical or nearly identical component that isillustrated in various figures may be represented by a like numeral. Forpurposes of clarity, not every component may be labeled in everydrawing. Various embodiments of the invention will now be described, byway of example, with reference to the accompanying drawings, in which:

FIG. 1 illustrates the system architecture of networked instruments inaccordance with one embodiment;

FIG. 2 illustrates multiple instruments of FIG. 1 in operablecommunication with an analytics module in accordance with oneembodiment;

FIG. 3 is a schematic of an illustrative embodiment of a network-enabledcell culture incubator in accordance with one embodiment;

FIG. 4 illustrates a system that may be implemented on a network of FIG.1 in accordance with one embodiment;

FIG. 5 illustrates the components of FIG. 4 in accordance with oneembodiment;

FIG. 6 illustrates various services in accordance with one embodiment;

FIG. 7 illustrates a plurality of network-enabled cell cultureincubators interoperating in accordance with one embodiment;

FIG. 8 depicts a flowchart of a method for operating a network-enabledcell culture incubator in accordance with one embodiment;

FIG. 9 is a software architecture diagram in accordance with oneembodiment;

FIG. 10 illustrates a network in accordance with another embodiment;

FIG. 11 illustrates the architecture of the hub of FIG. 10 ; and

FIG. 12 illustrates an example of the use of the hub in a laboratory.

DETAILED DESCRIPTION

Aspects of the disclosure relate to automated incubators that enableproductive long-term cell culture. It has been appreciated that, sincetraditional cell culture incubators require significant amounts of humanintervention, the traditional incubation process is subject to myriadsources of error that can disrupt culture growth. For example, themistaken introduction of items into an incubator by an operator from theexternal environment at the incorrect time or the incorrect stage of theincubation process can negatively affect the health or activity of asample. Similarly, an operator's failure to follow the timing or orderof steps specified by a protocol can kill a culture outright orinvalidate the results of the culturing process.

According to one aspect, a cell culture incubator is equipped with acontrol system, a network interface, a non-transient storage, and one ormore electrically controllable resources. These incubators may include avariety of such components, such as but not limited to sensors,environmental control systems, fluidics transport systems, robotics,etc., which may operate together at the direction of a computer,processor, microcontroller or other computing device. The control systemcontrols the cell culture incubator and automatically monitors andadjusts cell culture conditions for optimal growth of the cell culture.

The control system can be programmed with a variety of protocols storedin the non-transitory storage medium, manually entered by an operator,or retrieved from an external data source using the network interface.Each protocol describes how the control system should operate theelectrically controllable resources to incubate a particular cell lineor culture. Each individual protocol will have its own duration, whichmay itself vary during execution, depending on the protocol's purpose.

Protocols may be shared directly among network-enabled cell cultureincubators in a peer-to-peer arrangement or indirectly using, e.g., ahub-and-spoke type arrangement with a centralized repository ordatabase. Protocols may also be stored for later reuse by the samenetwork-enabled cell culture incubator. A protocol that is executed byone incubator may be manually or automatically associated with variousmetadata describing various aspects of the protocol, including but notlimited to incubator type, cell type, date of run, time of run, whetherthe run concluded successfully, conditional steps performed by the run,etc., to facilitate future storage, retrieval, indexing, and search. Theassociation of a protocol with various items of metadata may itself besemi-automated by copying some or all of the metadata associated with asimilar protocol.

As a protocol executes, a variety of systems may collect various formsof data concerning the execution of the protocol. Examples of collecteddata include ambient environmental data (temperature, gas levels,humidity, etc.), sampled sensor data (pH; images of cells, wells, etc.,using various imaging modes at various resolutions, etc.), valuesderived from image data (e.g., cell proliferation estimates, cellmorphology, stem cell colony growth, etc.), other raw and processed data(e.g., flow cytometry, various other assays), and additionalprotocol-related data (which parts of the incubator are used, when theyare used, how long they are used for; what volume of liquids aredispensed, when they are dispensed; bar code scans of various plates andconsumables as they move through the incubator, etc.).

This data may be associated and directly or indirectly shared with otherincubators in the same manner that protocols and metadata are shared, asdiscussed in greater detail below. As with protocols, each data set maybe manually or automatically associated with various metadata describingvarious aspects of the data set, including but not limited to incubatortype, cell type, date of run, time of run, whether the run concludedsuccessfully, conditional steps performed by the run, protocol executed,protocol parameters used, instruments used, instrument components used,etc., to facilitate future storage, retrieval, indexing, and search. Thedata collection processes may be automated, e.g., by the protocol,manually specified, or both. The association of a data set with variousitems of metadata may itself be semi-automated by copying some or all ofthe metadata associated with a similar data set.

One or more control systems may be interconnected by one or morenetworks in any suitable form, including as a local area network (LAN)or a wide area network (WAN) such as an enterprise network or theInternet. Such networks may be based on any suitable technology and mayoperate according to any suitable protocol and may include wirelessnetworks, wired networks, or fiber optic networks.

The various methods or processes outlined herein may be coded assoftware that is executable on one or more processors that employ anyone of a variety of operating systems or platforms. Such software may bewritten using any of a number of suitable programming languages and/orprogramming or scripting tools and may be compiled as executable machinelanguage code or intermediate code that is executed on a framework orvirtual machine.

One or more algorithms for controlling methods or processes providedherein may be embodied as a readable storage medium (or multiplereadable media) (e.g., a non-volatile computer memory, one or morefloppy discs, compact discs (CD), optical discs, digital versatile disks(DVD), magnetic tapes, flash memories, circuit configurations in FieldProgrammable Gate Arrays or other semiconductor devices, or othertangible storage medium) encoded with one or more programs that, whenexecuted on one or more computing units or other processors, performmethods that implement the various methods or processes describedherein.

In various embodiments, a computer readable storage medium may retaininformation for a sufficient time to provide computer-executableinstructions in a non-transitory form. Such a computer readable storagemedium or media can be transportable, such that the program or programsstored thereon can be loaded onto one or more different computing unitsor other processors to implement various aspects of the methods orprocesses described herein. As used herein, the term “computer-readablestorage medium” encompasses only a computer-readable medium that can beconsidered to be a manufacture (e.g., article of manufacture) or amachine. Alternatively or additionally, methods or processes describedherein may be embodied as a computer readable medium other than acomputer-readable storage medium, such as a propagating signal.

The terms “program” or “software” are used herein in a generic sense torefer to any type of code or set of executable instructions that can beemployed to program a computing unit or other processor to implementvarious aspects of the methods or processes described herein.Additionally, it should be appreciated that according to one aspect ofthis embodiment, one or more programs that when executed perform amethod or process described herein need not reside on a single computingunit or processor but may be distributed in a modular fashion amongst anumber of different computing units or processors to implement variousprocedures or operations.

Executable instructions may be in many forms, such as program modules,executed by one or more computing units or other devices. Generally,program modules include routines, programs, objects, components, datastructures, etc., that perform particular tasks or implement particularabstract data types. Typically, the functionality of the program modulesmay be organized as desired in various embodiments.

Turning to the figures, FIG. 1 illustrates a system 100 of networkedinstruments in accordance with one embodiment. The system 100 mayinclude one or more of a local area network 102 (LAN; e.g., an Intranet)and/or a wide area network 104 (WAN; e.g., the Internet). As can beseen, the LAN 102 and the WAN 104 may be in operable communication witheach other.

The LAN 102 may include databases 106 and 108. Although the LAN 102 isillustrated as including two databases, the LAN 102 may include anynumber of databases that may store a variety of types of data and in avariety of different formats.

The databases may or may not be in communication with user interfaces.For example, database 108 may be in operable communication with acustomer user interface 110. The customer user interface 110 may allowusers to query the databases for information such as data related tooperation of one or more instruments. The customer user interface 110may then present the information to the user.

The databases 106 and 108 may be in further communication withinstruments 112 and 114, respectively. These instruments 112 and 114 maybe a cell culture incubator device or any type of component includedwith or otherwise used in conjunction with an incubator device. Althoughthe LAN 102 is illustrated as including two instruments, the LAN 102 mayinclude any number of instruments. Additionally, a particular databasemay be in operable communication with any number of instruments.

The WAN 104 may also include one or more databases 116. The database 116may be similar in configuration to databases 106 and 108. The database116 may also be in operable communication with a customer user interface118. The customer user interface may be similar in configuration to thecustomer user interface 110 of the LAN 102 and may allow a user torequest and receive data stored in the database 116. The WAN 104 mayalso include or otherwise be in communication with one or moreinstruments 120. The instrument 120 may be similar in configuration tothe instruments 112 and 114 of the LAN 102.

The customer user interfaces 110 and 118 may be any sort of interfacethat allows one or more users to input commands, data, queries, or othertypes of information that may relate to one or more instruments andoperations. The customer user interfaces 110 and 118 may be configuredas, for example and without limitation, PCs, laptops, mobile phones,tablets, smartwatches, or any other devices that may receive informationfrom and present information to users. For example, users may inputinstructions for one or more instruments and/or receive data related tooperation of one or more instruments.

Examples of output devices that can be used to provide a user interfaceinclude printers or display screens for visual presentation of output,and speakers or other sound generating devices for audible presentationof output. Examples of input devices that can be used for a userinterface include keyboards and pointing devices, such as mice,touchpads, and digitizing tablets. In other examples, a computer mayreceive input information through speech recognition or in anotheraudible format, through visible gestures, through haptic input (e.g.,including vibrations, tactile and/or other forces), or any combinationthereof.

The databases may be configured as structured or non-structureddatabases and may be located in an incubator's non-transitory storage orremotely in a network accessible storage (e.g., NAS, SAN, etc.). Thedatabases may permit entire data sets, partial data sets, individualentries in a data set, or the like, to be retrieved using a specifiedindex value or a range of values. The data sets may also be stored witha hosted service provided by, e.g., a web-accessible server, therebyenabling data set sharing among networked incubators.

FIG. 2 illustrates an exemplary embodiment in which one or moreinstruments 114 are in operable communication with an analytic servicemodule 124. The service module 124 may include or otherwise be incommunication with a database 126 such as the databases 106, 108, or 116of FIG. 1 . The analytic service module 124 may further include a userinterface and dashboard component 128, an application programminginterface (API) 130, and an analytics engine 132.

In operation, the analytic service module 124 may issue commands to oneor more instruments 114 regarding tasks to be performed. For example, auser such as a lab worker may input instructions via the user interfaceand dashboard 128 which are communicated to the appropriate instrument114 via the API 130. The analytics engine 132 may gather, analyze, andpresent data regarding the instruments' operation in performing variousassigned tasks. This data may be shared amongst other instruments and/orstored in the database 126. Accordingly, multiple instruments maycommunicate with each other and the analytics engine 132 may analyze,process, and communicate data regarding instrument operations. Theinstruments may be configured as cell culture incubators such as the oneillustrated in FIG. 3 . The cell culture incubator 200 may include anincubator cabinet 202 having a transfer chamber 220 and an internalchamber 230. An electrically controllable external door 212 opens andcloses to permit communication between the transfer chamber 220 and theexternal environment (e.g. the environment external to the incubatorcabinet 202). An electrically controllable transfer chamber door 214opens and closes to permit communication between the transfer chamber220 and the internal chamber 230.

The transfer chamber 220 and/or the internal chamber 230 may include oneor more electrically controllable sensors for determining variousinternal conditions such as, but not limited to, temperature, humidity,gas content, pressure, and light levels. The transfer chamber 220 and/orthe internal chamber 230 may include electrically controllablecomponents for adjusting such internal conditions, such as a heater,humidifier, gas generator, air pump, etc.

In some embodiments, an electrically controllable transfer device ispositioned within the internal chamber 230. In other embodiments, anelectrically controllable transfer device may be positioned within thetransfer chamber 220. In yet other embodiments, the transfer device ispositioned in both the transfer chamber and the internal chamber. Inother embodiments, the transfer device can freely move between thechambers (such as with a robot that can move between the chambers).

In the illustrative embodiment shown in FIG. 3 , an electricallycontrollable transfer device 250 moves one or more items between thetransfer chamber 220 and the internal chamber 230. The transfer device250 may reach into transfer chamber 220, pick up one or more items fromthe transfer chamber 220, and move the item(s) into the internal chamber230. The transfer device 250 may be a robotic arm or any other suitabletransfer device described herein.

In some embodiments, more than one transfer device may be included inthe cell culture incubator cabinet 210. In the illustrative embodimentshown in FIG. 3 , in addition to the transfer device 250 of the internalchamber 230, an electrically controllable transfer device 240 isincluded in the transfer chamber 220. The transfer device 240 in thisembodiment may be a belt conveyor system that conveys items from one endof the transfer chamber 220 to the other end of the transfer chamber220. As one illustrative example, a computing unit 210 opens externaldoor 212 and places an item on the transfer device 240. The computingunit 210 directs the transfer device 240 to convey the item towardstransfer chamber door 214, which the computing unit 210 opens to receivethe item. The computing unit 210 directs the robotic arm 250 of theinternal chamber 230 to move the item off the transfer device 240 and toan appropriate location in the internal chamber 230. Alternatively, theitem falls off the conveyor 240 as it approaches the end of the conveyorand lands in internal chamber 230. The computing unit 210 may move theitem within the internal chamber 220 by a robotic arm 250 or othertransfer device.

In some embodiments, one or more resources in an incubator cabinetand/or on a transfer device may be used by a computing unit 210 tolocate and/or align the transfer device. In some embodiments, a locationor alignment component may be a physical feature (e.g., one or moreprotrusions, indentations, guides, etc., or any combination thereof). Insome embodiments, a location or alignment component may be electricallycontrollable by a computing unit 210, such as a signal and/or sensor(e.g., a laser, a camera, an ultrasonic range finder, etc., or anycombination thereof).

It should be appreciated that other types of transfer devices may beused as part of the cell culture incubator 200. For example, in oneembodiment (not shown), the cell culture incubator 200 includes atransfer device that includes an electrically controllable linearlyactuated receptacle. In this embodiment, the transfer device includes ahousing and a receptacle that is translated through the housing using anactuator that is electrically controllable by a computing unit 200.Using the actuator, the computing unit 210 moves the receptacle from oneend of the device to the other end of the device. The receptacle canextend at least partially through a first opening at the first end ofthe transfer device and through a second hole at the second end of thedevice.

In yet another embodiment (not shown), the transfer chamber 220 includesan additional electrically controllable robotic arm type transferdevice. It should be appreciated that any number and any type oftransfer devices may be included in an incubator (e.g., within one ormore chambers of an incubator cabinet). These transfer devices may varyin size and configuration as well.

As described herein, a computing unit 210 may control a sterilizationprocess within transfer chamber 220 to sterilize any items added intothe transfer chamber 220 from the external environment. In oneembodiment, a sterilization medium is used as part of the sterilizationprocess. Referring again to FIG. 3 , an electrically controllablesterilization medium source 260 is in fluid communication with thetransfer chamber 220. A pump 262 is used by a computing unit 210 toconvey sterilization medium from the sterilization medium source 260 tothe transfer chamber 220. Alternatively or in addition, the computingunit 210 may use the electrically controllable pump 262 to movesterilization medium from the transfer chamber 220 to the sterilizationmedium source 260. It should be appreciated that pump 262 may beintegrated with the source 260 itself. In some embodiments, no pump isincluded at all.

In one embodiment, the sterilization medium used is ozone. However, itshould be appreciated that other types of sterilization medium andcorresponding source may be used other than ozone. As such,sterilization medium source 260 may be a source of any suitablesterilization medium.

The computing unit 210 may use the sterilization medium provided to thetransfer chamber to sterilize the incubator cabinet or other parts ofthe incubator as part of a cleaning cycle. In one embodiment, during acleaning cycle, sterilization medium provided by the source 260 isintroduced by a computing unit 210 into the transfer chamber 220 tosterilize the chamber itself. The computing unit 210 may maintain theinternal door 214 in a closed state to prohibit sterilization mediumfrom entering internal chamber 230.

In another embodiment, a computing unit 210 sterilizes both the transferchamber 220 and the internal chamber 230 utilizing various electricallycontrollable resources. During a cleaning cycle, the computing unit 210may open the internal door 214 while ozone gas or other sterilizationmedium is generated or provided from source 260. With the internal door214 open, sterilization medium may enter into both transfer chamber 220and internal chamber 230.

With continued reference to FIG. 3 , the computing unit 210 may directlyroute sterilization medium to internal chamber 230. The sterilizationmedium flow path includes one or more flow controllers 223, 233 (such asvalves) that are used by the computing unit 210 to control thesterilization medium flow path. Flow controller 223 controls flowthrough a transfer chamber path 222 and flow controller 233 controlsflow through an internal chamber path 232. In one mode, wheresterilization medium is desired only in the transfer chamber 220, acomputing unit 210 closes flow controller 233 while the computing unit210 opens flow controller 223, and a computing unit 210 keeps theexternal door 212 and internal door 214 are closed. In another mode,where sterilization medium is desired only in the internal chamber, acomputing unit 210 closes flow controller 223, opens flow controller233, and closes internal door 214. In yet another mode, wheresterilization medium is desired in both chambers, a computing unit 210opens both flow controllers 223, 233 and closes external door 212. Thecomputing unit 210 may open or close internal door 214 in this mode.

As depicted in FIG. 3 , a computing unit 210 may be used to control oneor more components of the cell culture incubator 200. For example, thecomputing unit 210 may control the sterilization medium source 260, pump262 and/or 264, external door 212, internal door 214, transfer device240, 250 and/or 270, sensors, and any components that affect theinternal conditions of the incubator (e.g., heaters, humidifiers, gasgenerators, etc.). The computing unit 210 may be external to theincubator cabinet 202, as seen in FIG. 3 . The computing unit 210 mayreceive information from one or more sensors located inside theincubator cabinet 210 (sensors may be in the transfer chamber 220 and/orthe internal chamber 230). The computing unit 210 may communicate withone or more components of the cell culture incubator 210 and/or thesensors via wireless signals and/or wired signals.

As described herein, the computing unit 210 uses the electricallycontrollable resources of the incubator to provide and maintainappropriate temperature and gas mixtures for cell growth. It should beappreciated that cell growth conditions differ for different cell typesand that the incubators described herein can be programmed to maintaindifferent conditions that are appropriate for each cell type.

In some embodiments, the computing unit 210 and the electricallycontrollable resources described herein monitor or assay culture mediafor nutrient depletion, changes in pH, changes in temperature,accumulation of apoptotic or necrotic cells, and/or cell density. Insome embodiments, the computing unit 210 and the electricallycontrollable resources described herein are used to modify or change theculture media or conditions and/or to passage the cell cultures whenappropriate. In some embodiments, these procedures are automated.

Other electrically controllable resources may include in variousembodiments, for example, a liquid handling device (e.g., a pump, apipettor, etc.), a delivery system for delivering culture vessels orother components to or from the incubator, an environmental controlsystem for controlling the temperature, humidity, CO2 concentration,barometric pressure, and other environmental aspects of the incubator, adoor operation system, an imaging or detection system, and a cellculture assay system. In some embodiments, a means for detectingconditions in the medium is connected to or included in the incubator.In some embodiments, a processor is connected to or included in theincubator. In some embodiments, a non-transitory computer-readablemedium is connected to or included in the incubator. The medium hasinstructions stored thereon operable on one or more processors to adjustthe operation of the incubator system utilizing received parameter data.

In various embodiments, the electrically controllable resources of theincubator 200 may include, but are not limited to, one or more airlocks,doors, locks, interlocks, sterilizing means (e.g., O3 generators, HOgenerators, heat, radiation, etc.), light sources, environmental controlsystems (controlling temperature, humidity, atmospheric gas composition,etc.), imaging systems (cameras, microscopes, holographic imagers,etc.), sensors (temperature, air purity, contaminant levels, pH,humidity, N2, CO2, O2, O3, HO, CO, light, meters, etc.), monitoringsystems (oxygen monitors, carbon dioxide monitors, ozone gas detectors,hydrogen peroxide monitors, multi-gas monitors, etc.), filtrationsystems (fluid, gas, etc.), auxiliary systems (window wipers, controls,pumps, valves, apertures, etc.), positioning systems (laser light,wireless, etc.) and transfer devices (conveyor belt, robotic arms,etc.). For example, the airlock and doors may be opened or closed, allusing various electrical signals issued by a computing unit 210, eitherdirectly by the unit or indirectly by an interface that adjusts thesignals issued by the computing unit 210 to the voltages, currents,durations, protocols, etc., required to operate the resource.

In various embodiments each of these resources can be associated with anincubator (e.g., fitted within an incubator cabinet), incorporated aspart of an incubator (e.g., attached to, integral to, or otherwiseconnected to an internal wall or door of an incubator), or positioned ata suitable location(s) outside or inside an incubator cabinet (e.g.,within a transfer chamber and/or an internal chamber, for exampleattached to an internal wall, and/or upper or lower internal surface).

The above discussions regarding the incubator 200 relate to merelyexemplary embodiments of the instruments shown in FIG. 1 and referred tothroughout the application. Other types of devices may similarly be usedin accordance with the various features of the invention.

FIG. 4 illustrates a system 300 that may be implemented on network 102or 104 of FIG. 1 , for example. The system 300 may operate on orotherwise in conjunction with one or more servers 302 such as alaboratory information management system (LIMS) or an electronic labnotebook (ELN). The system 300 may include user interfaces 304 such as acustomer user interface 306 and a cell and reagent loading userinterface 308 that are accessible by one or more of scientists 310and/or administrators 312.

The user interfaces 304 may be similar in configuration to the userinterfaces of FIGS. 1 and 2 . The user interfaces 304 may be incommunication with an application programming interface 314 managed by asoftware engineer(s) 316 to at least communicate instructions to aninstrument control system (ICS) 318. The ICS 318 may be in communicationwith one or more databases 320, and may issue commands/instructions toone or more device services 322 (e.g., relating to incubators,refrigerators, etc.) and image processing services 324. The system 300may also include a controls diagnostic user interface 326 accessible bya field service engineer 328. The controls diagnostic user interface 326may allow the field service engineer(s) 328 to perform any maintenance,adjustments, or configurations to the various hardware devices.

In various embodiments, control of the operations of a cell cultureincubator by the instrument control system 318 may be implemented usinghardware, software, or a combination thereof. When implemented insoftware, the software code can be executed on any suitable processor orcollection of processors, whether provided in a single computing unit ordistributed among multiple computing units. Such processors may beimplemented as integrated circuits, with one or more processors in anintegrated circuit component. A processor may be implemented usingcircuitry in any suitable format. A typical processor is an x86, x86-64,ARMv7 processor, and the like. In various embodiments, the ITC 318controls various processes performed inside the incubator. For example,the computing unit may issue various signals controlling the operationor the state of various electrically-controllable resources contained inor in communication with the incubator (e.g., a manipulator, an imager,a fluid handling system, etc.). In some embodiments, the ITC 318controls imaging of cell cultures, picking of cells, weeding of cells(e.g., removal of cell clumps), monitoring of cell culture conditions,adjustment of cell culture conditions, tracking of cell culture vesselmovement within the incubator, and/or scheduling of any of the foregoingprocesses.

In various embodiments, the ITCs 318 operate each of the electricallycontrollable resources in an “open loop” fashion, i.e., without feedbackconcerning the operation of the resource. For example, the computingunit may operate (i.e., enable, disable, actuate, etc.) each resourceaccording to a pre-programmed schedule without accounting for the effectof the operation.

In various embodiments, the ITCs 318 may also operate a resource in a“closed loop” fashion utilizing an appropriate input (e.g., value,signal, etc.) from a sensor or other monitoring system. For example, theenvironment of the incubator may be modulated or controlled based uponinformation provided by one or more sensors. If an ITC 318 detects via aCO₂ sensor that the level of CO₂ in an incubator is lower than thatrequired by an executing protocol, then the computing unit may issue asignal to a CO₂ source to increase the level of CO₂ in the incubatoruntil the sensor indicates that the desired concentration of CO₂ hasbeen achieved. The same is true of, e.g., oxygen, humidity, etc., andany other parameter in the incubator that is subject to adjustmentutilizing one of the electrically controllable resources.

The ITC 318 may take any of a number of forms, such as a rack-mountedcomputer, a desktop computer, a laptop computer, a tablet computer, anembedded computer, a next unit of computing (NUC), etc., integrated intothe incubator or external to the incubator and communicating with via awired or wireless interface (e.g., gigabit Ethernet, 802.11x, etc.).Additionally, the ITC 318 may be a component not generally regarded as acomputer but capable of executing software providing appropriatefunctionality, such as a Personal Digital Assistant (PDA), a smart phoneor any other suitable portable, mobile or fixed electronic device,including the incubator itself.

FIG. 5 illustrates a networked system 400 such as the system 300 of FIG.3 in more detail. The system 400 may include at least one customer userinterface 402 and at least one cell and reagent loading user interface404 in communication with an application server 406. The customer userinterface 402 may be accessible by a user and similar in configurationto the customer user interfaces of FIG. 1 . The customer user interface402 may include various modules relating to operation of the incubatorssuch as, but not limited to, a protocol planning module 408, a datamanagement module 410, and a system administration module 412.

The protocol planning module 408 may allow a user to, via the customeruser interface 402, plan various protocols to be implemented by aninstrument. The customer user interface 402 may similarly present dataor other types of information regarding instrument operation.

The data management module 410 may perform tasks related to thedevelopment, execution, and management of various policies andprocedures required to appropriately manage data of the system 400.

The system administration module 412 may perform tasks related to orotherwise enable an administrator to configure and maintain operation ofthe various components of the system 400.

The customer user interface 402 may query the application server 406regarding instrument status and/or to send commands. These queries andinstructions may be communicated via web socket communication protocols.

The cell and reagent loading user interface 404 may also be incommunication with the application server 406. The cell and reagentloading user interface 404 may communicate with the application server406 via web socket communication protocols and may be separate from thecustomer user interface 402 because they're intended for differentpurposes. The cell and reagent loading user interface 404 may beconfigured as a tablet as part of or otherwise under the hood of a cellculture lab. Accordingly, the cell and reagent loading user interface404 may therefore facilitate the creation and labeling of plates withcells within the lab.

The application server 406 may subsequently publish commands orinstructions to the internet control system (ICS) 414. The ICS 414 maybe similar to the ICS 318 of FIG. 4 . The application server 406 maycommunicate these commands or instructions to the ICS 414 via web socketcommunication protocols and/or via the advanced message queuing protocol(AMQP).

Instructions may be communicated to the ICS 414. The ICS 414 may be incharge of passing along various instructions to an instrument (e.g., anincubator) regarding the instrument's operation. The ICS 414 may includea scheduling module 416, a protocol execution module 418, and aninventory management module 420, among others.

The scheduling module 416 may schedule various electrically controllableresources so as to execute one or more protocols. In variousembodiments, the scheduling module 416 accounts for the capabilities ofthe incubator, including the limited supplies of consumables (ascommunicated by the inventor management module 420), the dependency oflater operations on the successful completion of early operations, theability of the incubator to perform certain operations in parallel, thescheduled use of the incubator resources (e.g., transport resources) byanother protocol, the satisfaction of certain conditions prior toexecution, the time predicted for the completion of certain steps oroperations of the protocol, etc.

The protocol execution module 418 may be configured to issue commands tovarious electrically controllable resources in accordance withinstructions outputted by the scheduling module 416. The protocolexecution module 418 may similarly monitor the execution of variousprotocols and receive data regarding their execution.

The inventory management module 420 may be configured to monitor theinventory of the incubator and lab environment. The inventory managementmodule 402 may be configured to, for example, track the quantity ofvarious lab equipment or samples throughout a given period of time. Dataregarding the amount of resources may be communicated to the schedulingmodule 416 so that the scheduling module 416 can, based on the resourcesavailable at particular time, schedule certain protocols.

The application server 406 and the ICS 414 may also be in communicationwith one or more databases 422. The database(s) 422 may store dataregarding system and instrument operation, and may be configured as aNoSQL database, for example. Also, data structures may be stored incomputer-readable media in any suitable form. Non-limiting examples ofdata storage include structured, unstructured, localized, distributed,short-term and/or long-term storage. Non-limiting examples of protocolsthat can be used for communicating data include proprietary and/orindustry standard protocols (e.g., HTTP, HTML, XML, JSON, SQL, webservices, text, spreadsheets, etc., or any combination thereof). Forsimplicity of illustration, data structures may be shown to have fieldsthat are related through location in the data structure. Suchrelationships may likewise be achieved by assigning storage for thefields with locations in a computer-readable medium that conveysrelationship between the fields. However, any suitable mechanism may beused to establish a relationship between information in fields of a datastructure, including through the use of pointers, tags, or othermechanisms that establish relationship between data elements.

The ICS 414 may publish commands and receive data regarding events usingAMQP, for example. The message queue broker 424 essentially allows forthe various services of the instrument device 424 (discussed below) tointercommunicate. The message queue broker 424 may also be incommunication with a controls diagnostic user interface 426. Similar tothe ICS 414, the controls diagnostic user interface 426 may publishcommands and receive data regarding events using AMQP. The controlsdiagnostic user interface 426 may be accessible by, for example, one ormore field service engineers to enable them to perform any requiredmaintenance on the instrument or instrument components.

The instrument device 428 may include a system services layer 432 tocontrol the various modules 434-444 related to instrument operation.These modules may include, but are not limited to, a focus servicemodule 434 for focusing one or more sensors; a sensor service module 436for operating one or more sensor devices; a plate robot service module438 for operating a plate robot; a motor service module 440 foroperating one or more motors; a camera service module 442 for operatingone or more cameras; and a pipette service module 444 for operating oneor more pipettes.

In other words, the instrument device 428 may host the various servicesthat are capable of driving the various hardware components. Theseservices can be configured to execute at various levels of complexity.For example, a simple service may involve focusing a camera. A morecomplex service may involve multiple components, such as movement byseveral motors. Various components may of course receive instructionsfrom different services. For example, a pipette can listen to commandsfrom the motor service 440 and the pipette service 444. Accordingly, asingle hardware device can belong or otherwise listen to multipleservices.

The instrument device 428 therefore comprises two aspects. First, thehardware aspect, which includes various devices of the incubator.Second, the logical aspect, which comprises the various services thatenable the hardware to operate and perform various tasks.

The image processing module 430 may include an image processingintegration layer 46 to control the various modules 450-454 that arerelated to image processing. Certain tasks may require the analysis ofmultiple images collected over multiple time frames. Accordingly, thismay require coordination amongst various modules. These may include astitch routine module 444 that may be used to stitch images (e.g.,images of samples) together.

The pre-differential module 452 may be used to detect discrepanciesbetween stem cells during cell development. For example, stem cells aregenerally programmed to develop into a certain type of cell. However,oftentimes cells develop differently than expected. These discrepanciesin cells can spread to neighboring cells. Accordingly, thepre-differential module 452 may execute various novel algorithms todetect such discrepancies before they spread and impact neighboringcells.

These types of imaging-related modules are merely exemplary.Accordingly, it is contemplated that other modules configured to executealgorithms relating to image processing and analysis may be included andmay depend on the particular task. For example, FIG. 6 gives an overviewof several different types of services 600 that may be used inconjunction with different components and for different tasks. Theseservices may be in communication with a master control 602, which mayinclude components such as a user interface, application server, ICS,image processing service module, and one or more databases.

The action module 604 may include services related to movement andoperation of various devices of the incubator. For example, one or morepipettor services can be used to control movement of a pipette in the Z,X, and Y axes. Additional services that relate to pipette operation mayinclude motor one or more motor services and actuator services tocontrol movement of the pipette in various directions, one or moresensor services to gather information regarding the environmentsurrounding a pipette, one or more pump services to control liquid flow,and one or more scraper services to interact with a sample.

The action module 604 may also include services relating to imageprocurement and analysis. These may include camera services to controloperation of cameras (e.g., to focus one or more cameras), scannerservices to control scanners, plate transport services to controlmotions of plates (i.e., by operating one or more motors in variousaxes), gripper services to control grippers of plate transports,refrigerator services to control one or more refrigerators (and a motorservice to control movement of a refrigerator), and a message queueservice to receive and manage messages. The action module 604 may alsoinclude one or more services related to managing to the chain ofpossession of samples as well as services to verify digital signaturesof incoming messages.

The environmental module 606 may gather data regarding the incubator'senvironment. For example, to gather environmental information, anincubator device may include a user interface and a plurality of sensordevices controlled by a plurality of sensor services to capture dataregarding temperature, CO₂, O₂, pressure, etc.

The waste module 608 may include services related to waste management.For example, the waste module 608 may include a load cell service,actuator services, and sensor services to help detect and move waste.

Referring back to FIG. 3 , the network interface 204 permits theincubator 200 to communicate with other network-connected devices, suchas incubators, computers, network-enabled data sources, etc. Thecommunications may include transmitted and received messages, themessages including but not limited to shared data concerning protocols,protocol runs, protocol parameters, etc. The network interface 204 mayalso be configured to communicate one or more digital signatures toverify the authenticity of files or messages transferred betweeninstruments.

The network interface 204 of each instrument may also gather dataregarding analyzed samples. For example, features of various embodimentsof the present invention may include chip cards for storing data oncells leaving/entering a particular incubator. For example, a smart cardmay be configured on a plate and could be read by a system or incubatorreceiving that plate. Accordingly, this may act as a “check in” and“check out” system that monitors a particular plate and helps preservethe chain of custody of the plate.

Transmitting shared data to other network-connected devices enablesthose devices to re-share the data to other incubators or analyze theshared data, in particular image data. Receiving shared data permits theincubator(s) 200 to improve how they operate their protocols, makerecommendations concerning operations to the operator of the incubator200, etc.

FIG. 7 depicts a plurality of network-connected incubators 708-724, suchas the incubator of FIG. 3 , interacting so as to share various datasets, including but not limited to protocol, protocol results,associated metadata, etc. Sharing data sets permits individualincubators to share protocols, improve protocol operations, makerecommendations to individual human operators concerning protocolexecution, reanalyze prior runs, etc. Each incubator may also store itsown protocols and data sets for later reuse by that same incubator (notshown).

In some embodiments, the incubators 708-724 may be interconnected withother incubators and or network accessible data stores via LAN or WAN.The incubators may transmit various shared data sets (protocols,parameters, results, other metadata, etc.) to other incubators or thesedata stores to facilitate study and reuse of these data sets. The datastores may themselves share data sets to further facilitate study andreuse of the data sets.

As the data sets become more widely shared, either directly betweenincubators or indirectly using the data stores, individual incubatorscan use this shared data to improve protocol execution and outcomes.Individual incubators can rely exclusively on this shared data orutilize the shared data in combination with data local to the incubator,in some embodiments interacting with a plurality of shared data sourcesas if were a single shared data source.

The repository 700 may be a network-enabled data store, such as a NAS,SAN, network-enabled RAID array, web-hosted storage service (e.g., AWS),relational or object-oriented or other database, that permits data to bestored and retrieved by one or more devices using various networkcommunications. Repository 700 is connected to one or more incubators(e.g., incubator 708) via local area network connections (e.g.,Ethernet, Token Ring, etc.) and one or more incubators (e.g., incubator724) via wide area network connections (e.g., Internet or WAN 704). Theincubators may be the form of incubator illustrated in FIG. 3 , or theymay be a different form of incubator implementing a common protocol fordata sharing and requests establishing compatibility with the incubatorsof FIG. 3 . For example, the protocol may allow for the specification ofvarious parameters that determine the data sets retrieved from arepository 700.

Incubator 708 is directly connected to repository 700, permittingincubator 708 to transmit various shared data sets to the repository 700and retrieve various data sets from the repository 700 by providing aquery with various parameters specifying the data sets of interest.

Incubator 712 is, like incubator 708, directly connected to therepository 700 and indirectly connected to incubator 508 by way ofrepository 700. Incubator 712 can transmit various data sets to therepository 700 and retrieve various data sets from the repository 700 byproviding a query with various parameters specifying the data sets ofinterest. Incubator 712 can also transmit various data sets to theincubator 708 and retrieve various data sets from the incubator 708 byproviding a query with various parameters specifying the data sets ofinterest to be relayed by repository 700.

Incubators 712, 716, and 720 are interconnected in a peer-to-peerconfiguration. This arrangement allows each of the incubators to sharedata sets with each other, transmitting data sets to and retrieving datasets from connected incubators as if one of the connected incubators isa repository. Since incubator 712 is also connected to repository 700,incubators 716 and 720 can communicate with repository 700 as well asrepository-connected incubator 708.

Incubator 724 is connected to repository 700 via WAN 704, permittingincubator 724 to transmit various shared data sets to the repository 700and retrieve various data sets from the repository 700 by providing aquery with various parameters specifying the data sets of interest viathe WAN 704.

Individual incubators can selectively choose the shared data that theyreceive or the received shared data that they use by specifying variousselection parameters that may be relevant to the protocol presentlyexecuting (or to be executed) on the incubator. The shared data sets maybe filtered to exclude those data entries that do not satisfy therelevant selection parameters.

The incubators 708-724 may utilize the shared data as it received or itmay use various derived values thereof (e.g., statistical derivatives,compilations, deep learning networks, etc.) in the protocols that itexecutes. For example, a shared data set may detail the typical time ittakes for a certain kind of cells to grow under certain conditions fromtheir current state to requiring passaging, permitting a protocol topredict that the current culture of those cells will require passagingin, e.g., 10 hours, scheduling appropriate imaging and image analysisfor that timeframe. If the current culture is not ready for passaging bythat time, the operator may be alerted. If the imaging system indicatesthat the cells are fully disassociated in an unusual amount of time, theimaging system may reimage the culture, image a different area of thewell, issue an alert to a user or another system, etc.

The incubators and/or shared data sources may use shared data sets fromone incubator to reanalyze and reinterpret prior runs from the same oranother incubator, especially images. Shared data sets may also beanalyzed and used to recommend choices and options to an operator, e.g.,which media to use for a particular cell line.

Protocols and data sets may be anonymized prior to sharing, making itdifficult or impossible for third parties to determine the originalsource (i.e., author or incubator) of the protocol or the data set. Theanonymization process may be performed by the original incubator priorto the transmission of the protocol or dataset, by the repository 700hosting the protocol or the data set for sharing, etc.

Each protocol may include a variety of conditional actions, i.e.,actions triggered upon the satisfaction of a particular condition.Examples of such conditions include, but are not limited to, a valuemeeting a particular value or falling within a particular range, theresult of an automated or semi-automated analytical technique (e.g.,image analysis, pH measurement, etc.), the result of a command receivedvia a user interface from an operator, etc. In various embodimentsparticular values of interest include absolute time, relative time,elapsed time, etc. The threshold values or ranges of interest may beprogrammed in advance or derived in an automated manner from variousdata sets, such as previous runs of the protocol currently beingexecuted, or other protocols executed in connection with the particularcell type of interest. Examples of such actions may include theoperation of a particular piece of electrically controllable equipment;the execution of another protocol, such as a sub-protocol or areplacement protocol; the communication of various information to anoperator or a computing unit. In various embodiments, a human operatoror a computing unit may alter the stored protocol to address variousoperating conditions or constraints.

In some embodiments, information related to the operation of theincubator (e.g., temperature, humidity, gas composition, images, cellculture conditions, etc., or any combination thereof) can be obtainedfrom one or more sensors associated with the incubator (e.g., locatedwithin the incubator cabinet, located within the incubator but outsidethe incubator cabinet, located in proximity to the incubator and inelectrical communication with the incubator or an associated computingunit, etc.), and can be stored in computer-readable media to provideinformation about conditions during a cell culture incubation. In someembodiments, the computer-readable media comprises a database. In someembodiments, said database contains data from a single incubator. Insome embodiments, said database contains data from a plurality ofincubators. In some embodiments, data is stored subject to varioussecurity mechanisms and protocols that render it resistant tounauthorized access and manipulation. In some embodiments, all datagenerated by the incubator(s) and related facilities are stored. In someembodiments, a subset of that data is stored.

FIG. 8 depicts a flowchart describing an exemplary embodiment of amethod 800 for operating a shared data repository as described herein.In this embodiment, a computing unit executes instructions stored on anon-transitory storage medium that, when executed, provide a databasefor storing various incubation related data sets (Step 800): protocols,protocol outcomes, protocol parameters, etc. The database itself may bestructured (e.g., SQL, or object-oriented) or unstructured (e.g.,Hadoop). The computing unit may be a single computing device or aplurality of interconnected computing devices.

The repository receives data from an incubator through a networkinterface (Step 804). The data may include various incubator relateddata sets: protocols, parameters for protocol operation, protocolresults, images, etc.

Having received the incubator data, the repository stores the receiveddata in the database (Step 808). In some embodiments, the data isanonymized prior to storage.

In further operation, the repository receives one or more requests forpreviously-stored incubator data via a network interface (Step 812). Arequest will typically include various parameters specifying the data ofinterest to facilitate retrieval of the data from the repository. Therequest may also include various security-related parameters that therepository may use to determine whether the requester is permitted toaccess the requested data.

Once the request is processed by the repository, the repositorytransmits the requested incubator data to the requester via a networkinterface (Step 816). Upon receipt, the requester typically uses thedata to, e.g., configure, adjust, or execute one or more protocols on anincubator.

FIG. 9 presents a diagram representative of the software architectureused in various embodiments of the present invention. The incubatorsoftware architecture typically includes a web server 900 which issuitable for various operations 902, e.g., the presentation ofinformation to an operator, the receipt of commands and parametersspecified by an operator, the execution of applications for dataprocessing and analysis, data logging, diagnostics, etc. In FIG. 9 theweb server 900 is shown as presenting a variety of user interfaces (UI):a UI for use by an administrator, a UI for use by a scientist, a UI foruse by the incubator operator, etc. Those user interfaces may be viewedby a user on a graphical display incorporated into the incubator, agraphical display on a device in communication with the incubator over alocal network connection, a WAN connection, etc.

The architecture also includes one or more mechanisms for data storage,e.g., structured, unstructured, object-oriented, etc. These mechanismsare represented by database 904. These mechanisms may receive dataoriginating locally with the incubator, data delivered over the networkaffecting the operation of the incubator, etc. These mechanisms may alsobe used as a source of data to be transmitted over the network foraffecting the later occupation of the incubator or other incubator. Themechanisms for data storage may be stored completely or in part on theincubator itself and may also incorporate data storage mechanisms storedon other computing resources, accessible via local or wide area networkconnection.

The software on the incubator 908 includes a variety of softwarecomponents that operate to provide the functionality described above.These components are depicted in FIG. 9 as organized in various levels,with each level operating as an interface 912 to the components below itfor the components above it.

The lowest level of the incubator software components 908 provide aninterface to the various hardware components of the incubator: controlof the robot portions of the incubator, an interface to the camera, aninterface to the incubator sensors, etc.

The next level of modules 908 interact with the hardware interfacecomponents to implement various higher order functionalities. Forexample, the sensor logging module interfaces with the sensor modules tocollect sensor data. The imaging support module interfaces with thecamera module to collect and provide camera images to other softwaremodules. The robot simulation, robot control, and failsafe modulesinteract with the robot control module to provide a set of well-definedoperations that may be invoked by other software modules.

The higher level modules 908 in turn interact with these modules toimplement the execution of protocols as discussed above: decomposing theprotocols into various operations, scheduling and planning the executionof those operations, exposing an interface that allows a user tomanually control the various operations of the incubator, etc.

The networking of the instruments also provides an opportunity toutilize the internet of things to reduce the errors by human operatorsand improve reproducibility of results. The network 30 in FIG. 10connects a plurality of instruments 20A-20N and a hub 10. The networkcan be a local area network, a wide area network, wired or wireless or acombination of the foregoing. In one embodiment the hub 10 can benetworked with other hubs 11, 12 using a separate network 31 or with thenetwork 30. The network 31 can be connected to a database 15 forarchiving the data from one or more hubs and can have one or moreservers 16 for analyzing the data in database 15 including regulatoryand tracking.

The hub architecture is shown by way of example in FIG. 11 . The mainpurpose of the hub is to collect ad store information from and relatingto cell operations on instruments in a laboratory or manufacturingfacility. The hub controller 41 in conjunction with the ROM 46 and RAM47 controls of the operation of the hub. Network interface 44 allows thehub to interface with the instruments to receive data from theinstruments and to send information to the instruments. To facilitatethe input of data to the hub, the hub can include a bar code reader 42for reading one dimensional and two-dimensional bar code such as QRcodes. An RFID reader 43 is also provided for sensing the RFID radios inthe badges of personnel so that the hub can record the comings andgoings of operators. It can also be used to keep track of largelaboratory equipment such as instruments, refrigerators, liquid nitrogentanks, etc., so that if one of these is removed or replaced by anotherpiece of equipment, that change will be recorded. The hub also haswireless interface transceivers 45 and 48 for Bluetooth and Wi-Firespectively in order to receive data from remote sensors and the like.

The hub can also include cameras 51 for recording a video or sequentialstill image record of the vicinity around the hub and store those imageswith the other data. The hub can be equipped with proximity sensors 50if the hub is in an area where it is accessible by an operator and canread radios on materials. Similarly, the hub can include its own sensorssuch as temperature sensors 50 for recording ambient temperatures in afacility. It is understood that while the hub has been described as afree-standing unit, it can be integrated into an instrument or otherdevice or it can be multiple devices disposed in instruments or mountedin a facility.

FIG. 12 shows one example of the use of the hub 10 in a laboratorysetting. The instruments in the labor include incubator 20A and cellimager 20B. A refrigerator 11 is used to hold materials such as incontainers C1-C3 and bottle B1. Plate P having cover L2 with cellstherein can be maintained in liquid nitrogen tank LNT or in refrigerator11. An operator O has a badge B which contains an RFID radio which isdetected by the RFID reader in the hub whenever the operator enters orleaves the room. Also contained in the laboratory are a number ofsensors S1-S5 for sensing ambient conditions in the vicinity such astemperature, humidity, oxygen content, pollution, and altitude. Thecamera 51 which can be part of the hub or external to it, records videoof the vicinity of instruments 20A and 20B. The container C1 is fittedwith proximity sensors on the lid L1 and the body so that a signal issent to the hub whenever the lid is removed from the container. In thisway if the operator inadvertently leaves the lid off for too long, thatinformation will be archived. The lid L2 and plate P are similarlyfitted with sensors to provide information as to when the lid L2 isremoved from the plate and for how long. Similarly, the refrigerator andthe containers are also fitted with, for example, RFID proximity sensorswhich send a signal whenever the containers are removed from therefrigerator. This will allow a record of an inadvertent failure torefrigerate. The plate P which can be held in the refrigerator or in thetank LNT, will also have a proximity sensor that interacts with one inthe tank and the refrigerator to indicate whenever the plate is removedfrom either the refrigerator or the tank. All of this data is fed to thehub which stores the data for each of the devices. If a test is runusing a reagent in container C3 and then a later test is run with thesame reagent which produces different results, one can query thedatabase to determine if the container had been properly maintained. Thebottle B1 can be fitted with a sensor to provide its location. Thereforeif the bottle is placed in a refrigerator, a technician can learn whichrefrigerator and which shelf holds the bottle. A GPS is provided todetermine the location of the laboratory including its elevation. Amicrophone M1 is used to record sounds in the vicinity of the microphoneand a clock T1 is used to note the actual time that operations areperformed and for how long.

In another embodiment, the cell culture images for a particular cultureare associated with other files related to the cell culture. Forexample, many cell incubators and have bar codes adhered thereto toprovide a unique identification alphanumeric for the incubator.Similarly, media containers such as reagent bottles include bar codes toidentify the substance and preferably the lot number. The files of imagedata, preferably stored as raw image data, but which can also be in acompressed jpeg format, can be stored in a database in a memory in theimager or in the hub along with the media identification, the uniqueincubator identification, a user identification, pictures of the mediaor other supplies used in the culturing, notes taken during culturing inthe form of text, jpeg or pdf file formats. In one embodiment thedatabase is a blockchain database. Alternatively, the database can bestored in the cloud using Apple iCloud, Amazon Cloud Services or theMicrosoft Cloud.

In one embodiment, an app runs on a smartphone such as an IOS phone suchas the iPhone 11 or an Android based phone such as the Samsung GalaxyS10 and is able to communicate with the imager or the hub by way ofBluetooth, Wi-Fi or other wireless protocols. The smartphone links tothe imager or the hub and the bar code reader on the smartphone can readthe bar code labels on the incubator, the media containers, the user idbadge and other bar codes. The data from the bar codes is then stored inthe database with the cell culture image files. In addition, the cameraon the smartphone can be used to take pictures of the cell cultureequipment and media and any events relative to the culturing to storewith the cell culture image files. Notes can be taken on the smartphoneand transferred to the imager either in text form or by way of scanningwritten notes into jpeg or pdf file formats.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognizeor be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,and/or methods, if such features, systems, articles, materials, and/ormethods are not mutually inconsistent, is included within the scope ofthe present invention.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, e.g., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B,” when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, e.g., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (e.g. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, e.g., to mean including but not limited to.

Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

Use of ordinal terms such as “first,” “second,” “third,” etc., in theclaims to modify a claim element does not by itself connote anypriority, precedence, or order of one claim element over another or thetemporal order in which acts of a method are performed, but are usedmerely as labels to distinguish one claim element having a certain namefrom another element having a same name (but for use of the ordinalterm) to distinguish the claim elements.

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

What is claimed is:
 1. A cell laboratory data collection method for collecting cell data from at least one cell culture incubator connected in a network, the method comprising the steps of: providing a plurality of sensors including at least one sensor for sensing ambient conditions in a laboratory wherein the at least one cell culture incubator is disposed, and at least one sensor for sensing the identity of a cell operation supply material held in a container and used in a cell operation in the at least one cell culture incubator, configuring a controller to receive data from the plurality of sensors and cell operation data relating to the status of cells being operated on in the at least one cell culture incubator; archiving the cell operation data and the data from the plurality of sensors in a database connected to the network; and in response to determining that there is a difference between the status of cells in a current cell operation in the at least one cell culture incubator and the status of cells of a past operation in the at least one cell culture incubator that has been archived, providing an alert to the user, and wherein the step of providing an alert to the user includes providing a comparison of ambient conditions data and cell operation supply material data from the plurality of sensors from the past operation and the current operation to account for the difference in status.
 2. The data collection method according to claim 1, wherein the cell operation is cell culturing and the status of cells comprises at least one of confluence and cell count.
 3. The data collection method according to claim 1, wherein the conditions related to the performance of operations on cells includes alerts.
 4. The data collection method according to claim 1, wherein the conditions related to the performance of operations on cells includes alerts to people.
 5. The data collection method according to claim 1, wherein the conditions related to the performance of operations on cells includes alerts to computers.
 6. The data collection method according to claim 1, wherein the controller is configured to capture multiple streams of data.
 7. The data collection method according to claim 1, wherein the controller is configured to capture multiple streams of data, analyze the data and transmit the analysis to the database as part of an archive.
 8. The data collection method according to claim 1, wherein the plurality of sensors includes at least one sensor on a base and one on a cover of a supply material container to indicate when the cover has been removed.
 9. The method according to claim 1, wherein the controller compares data from the plurality of sensors for a past operation with the data for a more recent operation including at least one of time of day, elevation, and ambient noise to account for any differences in the results of the more recent operation.
 10. The method according to claim 1, wherein the plurality of sensors includes at least one proximity sensor for sensing when a closure for a container of a supply material used in a cell operation has been removed and replaced.
 11. The method according to claim 1, wherein the plurality of sensors includes at least one proximity sensor for sensing when material used in a cell operation has been removed from a liquid nitrogen tank.
 12. The method according to claim 1, wherein the plurality of sensors includes at least one proximity sensor for sensing when a plate used in a cell operation has been removed from a refrigerator.
 13. The method according to claim 1, wherein the plurality of sensors includes at least one proximity sensor for sensing when a cover has been removed from a plate.
 14. The method according to claim 1, wherein the plurality of sensors further comprises sensors on a plurality of bottles to provide location information for each of the plurality of bottles.
 15. The method according to claim 1, wherein the plurality of sensors includes at least one temperature sensor for sensing ambient temperature conditions.
 16. The method according to claim 1, wherein the plurality of sensors further comprises at least one video camera for filming in the vicinity of at least one cell operations instrument.
 17. The method according to claim 1, further comprising a code reader for reading codes on articles used for cell operations and transmitting the data therefrom to the controller.
 18. The method according to claim 1, further comprising an RFID reader for reading RFID tags on at least one of people or materials in the vicinity of at least one cell operations instrument and transmitting the data therefrom to the controller.
 19. The method according to claim 1, the plurality of sensors further comprising a Bluetooth transceiver.
 20. The method according to claim 1, the plurality of sensors further comprising a Wi-Fi transceiver.
 21. The method according to claim 1, further comprising a network interface for receiving data from at least one instrument for performing cell operations.
 22. The method according to claim 1, the plurality of sensors further comprising at least one microphone for recording sound.
 23. The method according to claim 1, the plurality of sensors further comprising a global positioning system receiver for providing location information.
 24. The method according to claim 1, the plurality of sensors further comprising at least one accelerometer on cell culture plates.
 25. The method according to claim 1, the plurality of sensors further comprising a clock for providing time information.
 26. The method according to claim 1, further comprising a network interface for receiving data from at least one other instrument. 